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Therapy induced carboplatin-DNA adduct levels in human ovarian tumours in relation to assessment of adduct measurement in mouse tumours

Lookup NU author(s): Dr Emma Meczes, Huw ThomasORCiD, Professor Richard Edmondson, Professor Gareth Veal, Professor Alan Boddy

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Abstract

Despite an increasing understanding of the molecular mechanisms by which platinum drug DNA adducts interact with cellular processes, the relationship between adduct formation in tumours and clinical response remains unclear. We have determined carboplatin–DNA adduct levels in biopsies removed from ovarian cancer patients following treatment. Reliability of DNA adducts measurements in tissues samples were assessed using experimental animals. Platinum–DNA adducts levels were measured using inductively coupled plasma mass spectrometry (ICP-MS) and plasma drug concentrations determined by atomic absorption spectrometry. Adduct levels in tissues and plasma pharmacokinetics were determined in Balb/c mice exposed to platinum drugs. Comparisons of adduct levels in tumour and normal tissue were made in nu/nu mice carrying human neuroblastoma xenografts. At 30 min post-cisplatin administration, adduct levels in DNA from kidney and liver were approximately 10- and 6-fold higher than spleen or tumour. By 60 min, levels in liver and kidney, but not spleen or tumour, had fallen considerably. Carboplatin showed high adduct levels only in kidney. Adduct levels in tumour xenografts were comparable to those induced in vitro with similar drug exposures. In clinical samples removed 6 h after drug administration, adduct levels ranged from 1.9 to 4.3 and 0.2 to 3.6 nmol Pt/g DNA for tumour biopsies and peripheral blood mononuclear cells, respectively. No correlation was apparent between these two data sets. The present results demonstrate that reliable measurements of adducts in clinical tumours are feasible. Future results should provide insight into drug resistance.

Publication metadata

Author(s): Jarvis IWH, Meczes EL, Thomas HD, Edmondson RJ, Veal GJ, Boddy AV, Ottley CJ, Pearson DG, Tilby MJ

Publication type: Article

Publication status: Published

Journal: Biochemical Pharmacology

Year: 2012

Volume: 83

Issue: 1

Pages: 69-77

Print publication date: 01/01/2012

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968

Publisher: Elsevier Inc.

URL: http://dx.doi.org/10.1016/j.bcp.2011.10.005

DOI: 10.1016/j.bcp.2011.10.005

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